2-Aminonaphthalene derivatives and related glycogen phosphorylase inhibitors

ABSTRACT

Novel compounds are provided which are glycogen phosphorylase inhibitors which are useful in treating, preventing or slowing the progression of diseases requiring glycogen phosphorylase inhibitor therapy such as diabetes and related conditions (such as hyperglycemia, impaired glucose tolerance, insulin resistance and hyperinsulinemia), the microvascular complications associated with diabetes (such as retinopathy, neuropathy, nephropathy and delayed wound healing), the macrovascular complications associated with diabetes (cardiovascular diseases such as atherosclerosis, abnormal heart function, myocardial ischemia and stroke), as well as Metabolic Syndrome and its component conditions including hypertension, obesity and dislipidemia (including hypertriglyceridemia, hypercholesterolemia and low HDL), and other maladies such as non-cardiac ischemia, infection and cancer. These novel compounds have the structure  
                 
 
or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein W, R 1  and R 2  are defined herein.

This application claims the benefit of U.S. Provisional Application No.60/628,064, filed Nov. 15, 2004, incorporated herein by reference in itsentirety.

BACKGROUND OF THE INVENTION

Approximately 100 million people worldwide suffer from type II diabetes,which is typically characterized by hyperglycemia due to excessivehepatic glucose production and peripheral insulin resistance, the rootcauses for which are as yet unknown. Hyperglycemia is considered to bethe major risk factor for the development of diabetic complications,such as retinopathy, neuropathy, nephropathy and macrovascular disease.

Accordingly, hepatic glucose production is an important potential targetfor type II diabetes therapy. The liver produces glucose byglycogenolysis (breakdown of the glucose polymer glycogen) andgluconeogenesis (synthesis of glucose from 2- and 3-carbon precursors).Particularly, glycogenolysis is catalyzed in the liver, muscle and brainby tissue-specific isoforms of the enzyme glycogen phosphorylase. Priorstudies suggest that glycogenolysis may make an important contributionto hepatic glucose output in type II diabetes. See, for example, WO96/39384; WO 96/39385; EP 978279; Proc. Natl. Acad. Sci. USA 1998, 95,1776-1781; J. Med. Chem. 1998, 41, 2934-2938; Exp. Opin. Invest. Drugs2001, 10, 439-454; EP 1136071; and WO 03/37864. Thus, glycogenphosphorylase inhibitors are believed to be useful therapeutic agentsfor treating type II diabetes and delaying the onset of diabeticcomplications by decreasing hepatic glucose production and loweringglycemia, while providing minimal risk of hypoglycemia and weight gain.See Id.

Based on the aforementioned references and additional references, forexample, WO 96/39384; WO 96/39385; WO 00/47206; U.S. Pat. No. 5,952,322;WO 99/43663; EP 1088824; US 2001/0046958; EP 1149580; WO 01/23347; EP1177791; WO 99/26659; U.S. Pat. No. 5,998,463; EP 1136071; US2004/0002495 and EP 1041068, it is believed that glycogen phosphorylaseinhibitors may be useful in treating, preventing or slowing theprogression of diseases such as diabetes and related conditions (such ashyperglycemia, impaired glucose tolerance, insulin resistance andhyperinsulinemia), the microvascular complications associated withdiabetes (such as retinopathy, neuropathy, nephropathy and delayed woundhealing), the macrovascular complications associated with diabetes(cardiovascular diseases such as atherosclerosis, abnormal heartfunction, myocardial ischemia and stroke), as well as Metabolic Syndromeand its component conditions including hypertension, obesity anddislipidemia (including hypertriglyceridemia, hypercholesterolemia andlow HDL), and other maladies such as non-cardiac ischemia, infection andcancer.

SUMMARY OF THE INVENTION

In accordance with the present invention, 2-aminonaphthalenes andrelated compounds are provided that have the general structure offormula I:

wherein W, R¹ and R² are defined below.

The compounds of the present invention inhibit the activity of theenzyme glycogen phosphorylase. Consequently, the compounds of thepresent invention may be used in the treatment of multiple diseases ordisorders associated with glycogen phosphorylase activity, such asdiabetes and related conditions (such as hyperglycemia, impaired glucosetolerance, insulin resistance and hyperinsulinemia), the microvascularcomplications associated with diabetes (such as retinopathy, neuropathy,nephropathy and delayed wound healing), the macrovascular complicationsassociated with diabetes (cardiovascular diseases such asatherosclerosis, abnormal heart function, myocardial ischemia andstroke), as well as Metabolic Syndrome and its component conditionsincluding hypertension, obesity and dislipidemia (includinghypertriglyceridemia, hypercholesterolemia and low HDL), and othermaladies such as non-cardiac ischemia, infection and cancer.

Inhibitors of the glycogen phosphorylase enzyme are also described inU.S. patent applications Ser. Nos. ______, ______ and ______, titled“2-Amino-3-Functionalized Tetralin Derivatives and Related GlycogenPhosphorylase Inhibitors”, “2-Amino-1-Functionalized TetralinDerivatives and Related Glycogen Phosphorylase Inhibitors” and“2-Amino-4-Functionalized Tetralin Derivatives and Related GlycogenPhosphorylase Inhibitors”, respectively, having the same assignee as thepresent invention and filed concomitantly herewith.

The present invention provides for compounds of formula I,pharmaceutical compositions employing such compounds and for methods ofusing such compounds. In particular, the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound of formula I, alone or in combination with apharmaceutically acceptable carrier.

Further, in accordance with the present invention, a method is providedfor preventing, inhibiting or treating the progression or onset ofdiseases or disorders associated with the activity of the enzymeglycogen phosphorylase, such as defined above and hereinafter, wherein atherapeutically effective amount of a compound of formula I isadministered to a mammalian, i.e., human, patient in need of treatment.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Further, the present invention provides a method for preventing,inhibiting or treating the diseases as defined above and hereinafter,wherein a therapeutically effective amount of a combination of acompound of formula I and another compound of formula I and/or at leastone other type of therapeutic agent, is administered to a mammalian,i.e., human, patient in need of treatment.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention discloses novel compounds offormula I:

or stereoisomers or prodrugs or pharmaceutically acceptable saltsthereof, wherein:

W is a bicyclic heteroaryl of the structure

R¹, which may attach at any of the three positions of the WCONH-bearingring of the naphthalene ring system, is independently hydrogen, alkyl,aryl, arylalkyl, heteroarylalkyl, alkenyl, OR^(5A), OCO₂R⁶,OCONR^(5A)R^(5B), CN, CN₄R^(5A) (tetrazole), CO₂R^(5A), CONR^(5A)R^(5B),CONR^(5A)OR^(5B), NR^(5A)COCO₂R^(5B) or another hydrogen bonding group;

R², which may attach at any of the four positions on thenon-WCONH-bearing ring of the naphthalene ring system, is independentlyhydrogen, halo, trifluoromethyl, cyano, hydroxy, another hydrogenbonding group, alkyl, aryl, arylalkyl, heteroarylalkyl, alkoxy, aryloxyor alkenyl;

R³ and R⁴ are each independently hydrogen, halo, trifluoromethyl, cyano,alkyl or alkoxy; and

R^(5A) and R^(5B) are independently hydrogen, alkyl, arylalkyl,heteroarylalkyl or aryl, or R^(5A) and R^(5B) may optionally be cyclizedtogether to form a ring, wherein said ring may further be substitutedwith one to three additional hydrogen bonding groups; and

R⁶ is alkyl, aryl, arylalkyl or heteroarylalkyl; wherein when R¹ and R²are alkyl, aryl, arylalkyl, heteroarylalkyl, alkenyl, alkoxy or aryloxy,R¹ and R² may each independently be substituted with one to threehydrogen bonding groups.

Some preferred compounds are those in which W is:

Some more preferred compounds are those in which A is —CH—.

Some even more preferred compounds are those in which

R¹ is independently substituted alkyl, OR^(5A), OCONR^(5A)R^(5B), CN,CN₄R^(5A) (tetrazole), CO₂R^(5A), CONR^(5A)R^(5B) or NR^(5A)COCO₂R^(5B);

R² and R³ are hydrogen;

R⁴ is halo, trifluoromethyl or cyano; and R^(5A) and R^(5B) are hydrogenor alkyl.

Some additional preferred compounds of the present invention are thosein which:

the hydrogen bonding group is preferably selected from the set ofmonovalent hydrogen bonding groups consisting of OR^(5A), OCO₂R⁶,OCONR^(5A)R^(5B), CN, NO₂, CN₄R^(5A) (tetrazole), COCF₃, COR^(5A),CO₂R^(5A), CONR^(5A)R^(5B), CONR^(5A)OR^(5B), C(NR^(5A))NR^(5B)R^(5C),CONR^(5A)SO₂R^(5B), SOR⁶, SO₂R⁶, SO₃H, SO₂NR^(5A)R^(5B),SO₂NR^(5A)COR^(5B), SO₂NR^(5A)CONR^(5B)R^(5C), POR^(5A)R^(5B),PO₂R^(5A)R^(5B), PO₃R^(5A)R^(5B), PO₂R^(5A)NR^(5B)R^(5C), NR^(5A)R^(5B),NR^(5A)COR^(5B), NR^(5A)C(NR^(5B))R^(5C), NR^(5A)CO₂R⁶,NR^(5A)COCO₂R^(5B), NR^(5A)CONR^(5B)R^(5C),NR^(5A)C(NR^(5B))NR^(5C)R^(5D), NR^(5A)SO₂R^(5B),NR^(5A)CONR^(5B)SO₂R^(5C), NR^(5A)SO₂NR^(5B)R^(5C),NR^(5A)POR^(5B)R^(5C), NR^(5A)PO₂R^(5B)R^(5C), NR^(5A)POR₃R^(5C) andNR^(5A)PO₂R^(5B)NR^(5C)R^(5D), or the set of divalent hydrogen bondinggroups consisting of —O—, —CO—, —SO₂—, —NR^(5A)—, —CO₂—, —CONR^(5A)—,—SO₂NR^(5A)—, —OCONR^(5A), —NR^(5A)CONR^(5B)—, —N(COR^(5A))—,—N(CO₂R^(5A))—, —N(CONR^(5A)R^(5B))— and —N(SO₂NR^(5A)R^(5B))—;

wherein

R^(5C) and R^(5D) are each independently hydrogen, alkyl, arylalkyl,heteroarylalkyl or aryl; and

wherein R^(5A), R^(5B), R^(5C), R^(5D) or R⁶ may further be substitutedwith one to three additional hydrogen bonding groups; and wherein

two of R^(5A), R^(5B), R^(5C) or R^(5D) within the same hydrogen bondinggroup may optionally be cyclized together to form a ring, wherein saidring may further be substituted with one to three additional hydrogenbonding groups.

Preferred compounds also include those compounds in which:

W is

A is —CH—; and

R⁴ is halo, trifluoromethyl or cyano.

Some particularly preferred compounds are those in which W is5-chloroindol-2-yl.

Some more particularly preferred compounds are those in which thecompound is selected from the compounds of Table 1.

In another embodiment, the present invention relates to pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound of the present invention, alone or, optionally, in combinationwith a pharmaceutically acceptable carrier and/or one or more otheragent(s).

In another embodiment, the present invention relates to methods ofinhibiting the activity of the enzyme glycogen phosphorylase comprisingadministering to a mammalian patient, preferably a human patient, inneed thereof a therapeutically effective amount of a compound of thepresent invention, alone, or optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting or treating the progression or onset of diseasesor disorders associated with the activity of the enzyme glycogenphosphorylase comprising administering to a mammalian patient,preferably a human patient, in need of prevention, inhibition ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

Examples of diseases or disorders associated with the activity of theenzyme glycogen phosphorylase that can be prevented, inhibited, ortreated according to the present invention include, but are not limitedto, diabetes and related conditions (such as hyperglycemia, impairedglucose tolerance, insulin resistance and hyperinsulinemia), themicrovascular complications associated with diabetes (such asretinopathy, neuropathy, nephropathy and delayed wound healing), themacrovascular complications associated with diabetes (cardiovasculardiseases such as atherosclerosis, abnormal heart function, myocardialischemia and stroke), as well as Metabolic Syndrome and its componentconditions including hypertension, obesity and dislipidemia (includinghypertriglyceridemia, hypercholesterolemia and low HDL), and othermaladies such as non-cardiac ischemia, infection and cancer.

Definitions

The following abbreviations have the indicated meanings:

min=minute(s)

h or hr=hour(s)

L=liter(s)

mL=milliliter(s)

μL=microliter(s)

g=gram(s)

mg milligram(s)

mol mole(s)

M=molar

mmol=millimole(s)

HPLC=high performance liquid chromatography

HPLC/MS or LC/MS=high performance liquid chromatography/massspectrometry

MS or Mass Spec=mass spectrometry

[M+H]⁺=parent plus a proton

[M−H]⁻=parent minus a proton

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

The term “hydrogen bonding group(s)” describes functional groups thatmay form a hydrogen bond by either donating or accepting a hydrogenatom. Examples of suitable “hydrogen bonding group(s)” include, but arenot limited to the monovalent groups OR OCO₂R⁶, OCONR^(5A)R^(5B), CN,NO₂, CN₄R^(5A) (tetrazole), COCF₃, COR^(5A), CO₂R^(5B), CONR^(5A)R^(5B),CONR^(5A)OR^(5B), C(NR^(5A))NR^(5B)R^(5C), CONR^(5A)SO₂R^(5B), SOR⁶,SO₂R⁶, SO₃H, SO₂NR^(5A)R^(5B), SO₂NR^(5A)COR^(5B),SO₂NR^(5A)CONR^(5B)R^(5C), POR^(5A)R^(5B), PO₂R^(5A)R^(5B),PO₃R^(5A)R^(5B), PO₂R^(5A)NR^(5B)R^(5C), NR^(5A)R^(5B), NR^(5A)COR^(5B),NR^(5A)C(NR^(5B))R^(5C), NR^(5A)CO₂R⁶, NR^(5A)COCO₂R^(5B),NR^(5A)CONR^(5B)R^(5C), NR^(5A)C(NR^(5B))NR^(5C)R^(5D),NR^(5A)SO₂R^(5B), NR^(5A)CONR^(5B)SO₂R^(5C), NR^(5A)SO₂NR^(5B)R^(5C),NR^(5A)POR^(5B)R^(5C), NR^(5A)PO₂R^(5B)R^(5C), NR^(5A)PO₃R^(5B)R^(5C)and NR^(5A)PO₂R^(5B)NR^(5C)R^(5D), and the divalent groups —O—, —CO—,—SO₂—, —NR^(5A)—, —CO₂—, —CONR^(5A)—, —SO₂NR^(5A)—, —OCONR^(5A)—,—NR^(5A)CONR^(5B)—, —N(COR^(5A))—, —N(CO₂R^(5A))—, —N(CONR^(5A)R^(5B))—and —N(SO₂NR^(5A)R^(5B))—, and the like, wherein

R^(5A), R^(5B), R^(5C) and R^(5D) for each occurrence are eachindependently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl; and

R⁶ is alkyl, arylalkyl, heteroarylalkyl, or aryl.

Moreover, R^(5A-5D) and R⁶ may be further substituted with one to threehydrogen bonding groups. For example, by substitution with themonovalent hydrogen bonding group OH, CONR^(5A)R^(5B) may representCON(Me)CH₂CH₂OH. Optionally, two of R^(5A), R^(5B), R^(5C) or R^(5D)within the same hydrogen bonding group may be cyclized together to forma ring by joining the two R groups with either a bond or with a divalenthydrogen bonding group. For example, CONR^(5A)R^(5B) may representCON(CH₂CH₂CH₂CH₂), N-acylated pyrrolidine, or CON(CH₂CH₂NHCH₂CH₂),N-acylated piperidine. Said ring may further be substituted with one tothree additional hydrogen bonding groups, for example N-acylatedhydroxyproline or N-acylated 3,4-dihydroxypyrrolidine.

In addition, when an R group is itself equal to a hydrogen bondinggroup, said hydrogen bonding group is a monovalent hydrogen bondinggroup. However, when an R group is substituted with a hydrogen bondinggroup, said hydrogen bonding group may be either a monovalent or adivalent hydrogen bonding group.

Substitution of any single R group with a divalent hydrogen bondinggroup preferably forms a ring. For example, substitution of a 2-butylgroup at the 1- and 4-positions with —O— forms a 3-tetrahydrofuranylgroup. Substitution of a 1-pentyl group at the 1- and 5-positions with—CO— forms a 2-oxocyclohexyl group.

The term “alkyl” as employed herein, alone or as part of another group,includes straight chain, branched chain and saturated cyclichydrocarbons, containing 1 to 20 carbons, preferably 1 to 10 carbons,more preferably 1 to 8 carbons, in the normal chain, such as methyl,ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl,isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl,nonyl, decyl, undecyl, dodecyl, cyclopropyl, cyclohexyl, and the like.

Unless otherwise indicated, the term “alkenyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 2 to 12 carbons, and morepreferably 2 to 8 carbons in the normal chain, that include one or moredouble bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl,2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl,3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl.

Unless otherwise indicated, the term “aryl” or “Ar” as employed hereinalone or as part of another group refers to monocyclic and bicyclicaromatic groups containing 6 to 10 carbons in the ring portion (such asphenyl or naphthyl including 1-naphthyl and 2-naphthyl) and mayoptionally include one additional fused heterocyclic ring, for example:

Aryl groups as defined above may optionally be substituted with alkylgroups containing up to six carbons and/or with halogen groups.

The term “arylalkyl” as used alone or as part of another group refers toan alkyl as defined herein, having an aryl substituent. Representativeexamples of arylalkyl include, but are not limited to, benzyl,2-phenylethyl, 3-phenylpropyl, benzhydryl, naphthylmethyl,4-trifluoromethylphenylpropyl and the like.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine and iodine and also topseudohalogen groups such as trifluoromethyl, trifluoromethoxy anddifluoromethoxy.

Unless otherwise indicated, the term “alkoxy” or “aryloxy” as employedherein alone or as part of another group refers to an alkyl or arylgroup, as defined herein, linked to an oxygen atom.

Unless otherwise indicated, the term “heteroaryl” as used herein aloneor as part of another group refers to a 5- or 6-membered aromatic ringwhich includes 1, 2, 3 or 4 heteroatoms such as nitrogen, oxygen orsulfur, and includes possible N-oxides. Examples of heteroaryl groupsinclude the following:

and the like.

Heteroaryl groups as defined above may optionally be substituted withalkyl groups containing up to six carbons and/or with halogen groups.

As used herein, the term “heteroarylalkyl” means an alkyl group having aheteroaryl substituent.

The term “cyano” as used herein, refers to a —CN group.

An administration of a therapeutic agent of the invention includesadministration of a therapeutically effective amount of the agent of theinvention. The term “therapeutically effective amount” as used hereinrefers to an amount of a therapeutic agent to treat or prevent acondition treatable by administration of a composition of the invention.That amount is the amount sufficient to exhibit a detectable therapeuticor preventative or ameliorative effect. The effect may include, forexample, treatment or prevention of the conditions listed herein. Theprecise effective amount for a subject will depend upon the subject'ssize and health, the nature and extent of the condition being treated,recommendations of the treating physician, and the therapeutics orcombination of therapeutics selected for administration. Thus, it is notuseful to specify an exact effective amount in advance.

The compounds of formula I can be present as salts, which are alsowithin the scope of this invention. Pharmaceutically acceptable (i.e.,non-toxic, physiologically acceptable) salts are preferred. If thecompounds of formula I have, for example, at least one basic center,they can form acid addition salts. These are formed, for example, withstrong inorganic acids, such as mineral acids, for example sulfuricacid, phosphoric acid or a hydrohalic acid, with organic carboxylicacids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which areunsubstituted or substituted, for example, by halogen, for exampleacetic acid, such as saturated or unsaturated dicarboxylic acids, forexample oxalic, malonic, succinic, maleic, fumaric, phthalic orterephthalic acid, such as hydroxycarboxylic acids, for exampleascorbic, glycolic, lactic, malic, tartaric or citric acid, such asamino acids, (for example aspartic or glutamic acid or lysine orarginine), or benzoic acid, or with organic sulfonic acids, such as(C₁-C₄) alkyl or arylsulfonic acids which are unsubstituted orsubstituted, for example by halogen, for example methyl- orp-toluenesulfonic acid. Corresponding acid addition salts can also beformed having, if desired, an additionally present basic center. Thecompounds of formula I having at least one acid group (for example COOH)can form salts with bases. Suitable salts with bases are, for example,metal salts, such as alkali metal or alkaline earth metal salts, forexample sodium, potassium or magnesium salts, or salts with ammonia oran organic amine, such as morpholine, thiomorpholine, piperidine,pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl,tert-butyl, diethyl, diisopropyl, triethyl, tributyl ordimethylpropylamine, or a mono-, di- or trihydroxy lower alkylamine, forexample mono-, di- or triethanolamine. Corresponding internal salts mayfurthermore be formed. Salts which are unsuitable for pharmaceuticaluses but which can be employed, for example, for the isolation orpurification of free compounds of formula I or their pharmaceuticallyacceptable salts, are also included.

Preferred salts of the compounds of formula I which contain a basicgroup include monohydrochloride, hydrogensulfate, methanesulfonate,phosphate or nitrate salts.

Preferred salts of the compounds of formula I which contain an acidgroup include sodium, potassium and magnesium salts and pharmaceuticallyacceptable organic amine salts.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the invention.

The term “prodrug esters” as employed herein includes esters andcarbonates formed by reacting one or more hydroxyls of compounds offormula I with alkyl, alkoxy, or aryl substituted acylating agentsemploying procedures known to those skilled in the art to generateacetates, pivalates, methylcarbonates, benzoates and the like.

Various forms of prodrugs are well known in the art and are describedin:

-   a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al.,    Ch. 31, (Academic Press, 1996);-   b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson    and H. Bundgaard, eds. Ch. 5, pgs 113-191 (Harwood Academic    Publishers, 1991); and-   d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and    Joachim M. Mayer, (Wiley-VCH, 2003).    Said references are incorporated herein by reference.

In addition, compounds of the formula I are, subsequent to theirpreparation, preferably isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% formula Icompound (“substantially pure” compound I), which is then used orformulated as described herein. Such “substantially pure” compounds ofthe formula I are also contemplated herein as part of the presentinvention.

All stereoisomers and polymorphs of the compounds of the instantinvention are contemplated, either in admixture or in pure orsubstantially pure form. The compounds of the present invention can haveasymmetric centers at any of the carbon atoms including any one of the Rsubstituents and/or exhibit polymorphism. Consequently, compounds offormula I can exist in enantiomeric, diastereomeric, or polymorphicforms or in mixtures thereof. The processes for preparation can utilizeracemates, enantiomers, diastereomers or polymorphs as startingmaterials. When diastereomeric or enantiomeric products are prepared,they can be separated by conventional methods for example,chromatographic or fractional crystallization.

Synthesis

The compounds of formula I of the invention can be prepared as shownbelow in the following reaction schemes and description thereof, as wellas by using relevant published literature procedures that may be used byone skilled in the art. Exemplary reagents and procedures for thesereactions appear hereinafter and in the working Examples.

Compounds of formula I may be prepared by coupling carboxylic acids offormula II with amines of formula III using standard methods for amidebond formation, as known to those skilled in the art, for example, bytreating equimolar amounts of compounds II and III inN,N-dimethylformamide solution at room temperature with equimolaramounts of 1-hydroxy-7-azabenzotriazole and1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride.

Carboxylic acids II may be prepared according to the routes andprocedures described in WO 9639384, WO 9926659, and EP 1088824.

Amines III may be prepared by deprotection of the correspondingprotected amines IV, in which the amino group is protected (PGN) as acarbamate, amide, phthalimide, N-benzyl derivative, or other standardamine protecting group, such as described in Protective Groups inOrganic Synthesis (2^(nd) Edition, T. W. Greene and P. G. M. Wuts, JohnWiley & Sons, 1991).

Also included in the definition of protected amine IV are compounds inwhich the amino group is masked (PGN), i.e., the latent amino group maynot fall into the strict definition of a protecting group, such as anazido or nitro group. Protected amines IV wherein the amino group ismasked as a carbamate, amide, phthalimide, N-benzyl derivative, or otherstandard amine protecting group may be prepared from the amines III asdescribed in Protective Groups in Organic Synthesis. A reason forconverting an amine III to a protected amine IV would be to modify R¹and/or R² prior to deprotection to regenerate a different amine III.Azido, nitro, and some protected amino groups, such as benzylamino, maybe introduced by other means, such as displacement (azido andbenzylamino). Carbamates may be prepared not only from the correspondingamine, but also from carboxylic acids by Curtius rearrangement, via theacid chloride, acyl azide and isocyanate (see Comprehensive OrganicSynthesis, Editor B. M. Trost, Pergamon Press, 1991).

A number of especially useful amines III are commercially available orknown in the literature as shown in Chart I.

Additionally, the book The Chemistry and Technology of NaphthaleneCompounds (N. Donaldson, Edward Arnold Publishers, 1958) providesnaphthalene compound-specific synthetic information, particularly inchapters VII and XI, which discuss naphthylamines substituted with halo,nitro and hydroxyl groups. Another useful reference work for naphthalenecompound chemistry is volume III of Rodd's Chemistry of CarbonCompounds, Editor S. Coffey, Elsevier Publishing Company, 1971.

In general, the interchange of functional groups within R¹ and R²,including the formation of various hydrogen bonding groups, may beaccomplished according to the methods and procedures described inCompendium of Organic Synthetic Methods (John Wiley & Sons),Comprehensive Organic Functional Group Transformations (Editors A. R.Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press) andComprehensive Organic Transformations—A Guide To Functional GroupPreparations (R. C. Larock, VCH Publishers, 1989). For example, aprotected amine IV in which R¹ is 2-hydroxyethylaminocarbonyl may beprepared from the corresponding compound in which R¹ is a carboxyl groupby standard amide coupling chemistry using 2-hydroxyethylamine. Asanother example, a protected amine IV in which R¹ is an acylated aminogroup such as carboxycarbonylamino may be prepared from thecorresponding compound in which R¹ is a carboxyl group by Curtiusrearrangement followed by acylation with methyl oxalyl chloride andester hydrolysis with sodium hydroxide. It is understood that during thecourse of manipulating any functional group within R¹ and R², standardprotecting groups, as described in Protective Groups in OrganicSynthesis, may be employed to avoid undesired reaction of any otherfunctional group, or of the indole ring or other bicyclic heterocycle W,particularly at its nitrogen, or of the amide linking W to the rest ofthe molecule.

Standard protecting groups may be used at any stage of the synthesis,for example in manipulating a functional group to convert one compoundof formula I to another compound of formula I, or in manipulating afunctional group to convert one protected amine IV to another protectedamine IV, or to avoid undesired reaction during the coupling ofcarboxylic acid II and amine III, or during the sequence of stepsleading to the formation of either carboxylic acid II or protected amineIV.

As known to those skilled in the art, most functional grouptransformation chemistry that is effective for interconvertingsubstituents attached to an isolated benzene ring is also effective forinterconverting substituents on a naphthalene ring. Therefore, thegeneral references Compendium of Organic Synthetic Methods,Comprehensive Organic Functional Group Transformations and ComprehensiveOrganic Transformations—A Guide To Functional Group Preparations provideadequate information for one skilled in the art to effectinterconversions of functional groups within R¹ and R². Accordingly, inComprehensive Organic Transformations—A Guide To Functional GroupPreparations by Larock the transformation index keyword “arene” is usedto search the chemistry of transformations of functional groups attachedto either isolated benzene rings or naphthalene ring systems.

Table B below highlights some of the standard aromatic ring substituentfunctional group manipulations known to those skilled in the art thatare potentially useful for introduction or manipulation of R¹ or R² orthe reactive amino group in amines III. In certain entries the DesiredProduct Functional Group is marked with an asterisk (*). In these casesthe functional group is introduced ortho to a pre-existing functionalgroup such as PGN. Most of the references are attributed to Larock withthe page number on which the method appears in Comprehensive OrganicTransformations—A Guide To Functional Group Preparations. In Table B, LGrepresents a leaving group, especially chloride, bromide, iodide,methanesulfonate and trifluoromethanesulfonate, which is useful innucleophilic displacement and palladium catalyzed coupling reactions.The group M represents a monovalent metal atom or group that rendersnucleophilic the group to which it is attached. For example M may belithium as in butyl lithium, chloromagnesium as in benzylmagnesiumchloride, etc. The group R (lacking a superscripted numeral) representsan alkyl or benzyl group. TABLE B ArX → ArY Desired Starting ProductMaterial Group Y Group X Reagents Reference OH NH₂ NaNO₂, H₂SO₄ Larock483 b. H₂O, heat OH OR HBr, AcOH Larock 501 OH LG a. BuLi Larock 490 b.(Me₃SiO)₂ OH COCH₃ mCPBA Larock 843 b. NaOH CO₂H* H a. RLi b. CO₂ Larock50 CO₂H LG CO, ROH, Pd cat. Larock 855, 856 b. NaOH CO₂H CH₃ KMnO₄Larock 823 CO₂H CN HCl, H₂O Larock 993 CO₂H COCH₃ I₂, NaOH Larock 842NH₂ CO₂H SOCl₂b. NaN₃ Larock 431 c. H₂O, heat NH₂ NO₂ H₂, cat. Larock412 NH₂ LG RLib. H₂NOMe Larock 399 LG H Br₂ Larock 315 LG* H a. RLi b.I₂ Larock 50 LG OH Tf₂O, pyr OR LG NaOR, Pd cat. Mann and Palucki COCH₃H Ac₂O, Lewis acid Larock 703 CN LG CuCN Larock 861 NO₂ H HNO₃, H₂SO₄CH₂NH₂ CN BH₃ Larock 437

Schemes 1-5 set forth below are provided as non-limiting illustrationsof the breadth of possible synthetic manipulations. Scheme 1 illustratesR¹ manipulation. Scheme 2 illustrates R² manipulation. Scheme 3illustrates R¹ and R² manipulation. Scheme 4 illustrates amino groupinstallation. Scheme 5 illustrates amino group installation and R¹manipulation. For transformations that Table B does not address,standard reagents are included.

In the synthetic schemes set forth above, the reagent lists areabbreviated. References cited above provide full details and in somecases alternative reagents. It is understood that the reagents shown inthe synthetic schemes are example reagents, not meant to be limiting.Those skilled in the art will recognize that there are many acids(hydrochloric acid, polyphosphoric acid, etc.), many bases (sodiumhydride, potassium methoxide, etc.), many oxidants (hydrogen peroxide,3-chloroperoxybenzoic acid, Dess-Martin periodinane, etc.), manyhydrogenation catalysts (palladium, platinum oxide, Raney® Nickel,etc.), and so on that may be employed to synthesize the compounds of theinvention. In some cases alternative reagents known to those skilled inthe art will be superior to those listed in the synthetic schemes.Alternative reagents may be found in Reagents For Organic Synthesis(Fieser and Fieser, John Wiley & Sons) and Compendium of OrganicSynthetic Methods (John Wiley & Sons). These references will alsoprovide guidance in cases where the synthetic schemes designate only aclass of reagent rather than a specific reagent (for example oxidantrather than hydrogen peroxide). In some instances the synthetic schemesrefer not to specific reagents or reagent classes, but rather to namereactions, for example Suzuki coupling. These name reactions and theirexperimental details are well-known to those skilled in the art (seeOrganic Syntheses Based on Name Reactions and Unnamed Reactions, A.Hassner and C. Stumer, Pergamon Press, 1994).

The references provided are not intended to constrain the applicabilityof the reaction steps, but rather to exemplify the reactions and providefurther experimental detail. The references are designated by either apatent/publication number or the first author of a scientific journalpublication. Full scientific journal publication references according tofirst author are as follows: Mann, J. Org. Chem. 1997, 62, 5413-5418;Palucki, J. Am. Chem. Soc. 1997, 119, 3395-3396.

In the spirit of further illustration of the manipulation of functionalgroups within R¹ and R², compounds of formula I and protected amines IVwherein R¹ or R² is cyano, alkyl, aryl, arylalkyl, heteroarylalkyl,alkoxy, aryloxy or alkenyl may be prepared from compounds of formula Iand protected amines IV wherein R¹ or R² is halo or hydroxy, usingvarious palladium catalyzed coupling procedures as described in Aranyos,et al., J. Am. Chem. Soc. 1999, 121, 4369-4378 and Hamann, et al., J.Am. Chem. Soc. 1998, 120, 7369-7370 and references contained therein,and in recent papers authored by Gregory C. Fu, Stephen L. Buchwald, orJohn F. Hartwig. These procedures are directly applicable when R¹ or R²is halo. When R¹ or R² is hydroxy, prior activation by conversion of thehydroxyl group to a trifluoromethylsulfonyloxy group, as described inthe aforementioned references, is required.

Compounds of formula I and protected amines IV in which R¹ is OR^(5A),OCO₂R⁶ or OCONR^(5A)R^(5B), or wherein R² is substituted orunsubstituted alkoxy or aryloxy, may be prepared by elaboration of theanalogous compounds of formula I and protected amines IV wherein R¹ orR², respectively, is hydroxy. For instance, a compound wherein R¹ isbenzyloxy may be prepared by benzylation of the compound wherein R¹ ishydroxy with benzyl bromide. A compound wherein R² iscarbomethoxymethoxy may be prepared from the compound in which R² ishydroxy by alkylation with methyl bromoacetate. A compound wherein R² iscarboxymethoxy may be prepared by hydrolysis of the compound wherein R²is carbomethoxymethoxy or carbo-t-butyloxymethoxy. A compound wherein R²is 2-hydroxyethoxy may be prepared by reduction of the compound whereinR² is carbomethoxymethoxy or carboxymethoxy. A compound wherein R² is2,3-dihydroxypropyloxy may be prepared from the compound wherein R² ishydroxy by alkylation with glycidyl 3-nitrobenzenesulfonate, followed byepoxide hydrolysis. A compound wherein R² is aryloxy may be preparedfrom the compound in which R² is hydroxy and an aryl halide by variouspalladium catalyzed coupling procedures as described in Aranyos, et al.,J. Am. Chem. Soc. 1999, 121, 4369-4378 and references contained therein,and in recent papers authored by Stephen L. Buchwald.

The references above are incorporated herein by reference.

Utilities and Combinations

A. Utilities

The compounds of the present invention possess activity as inhibitors ofthe enzyme glycogen phosphorylase and therefore may be used in thetreatment of diseases associated with glycogen phosphorylase activity.Via the inhibition of glycogen phosphorylase, the compounds of thepresent invention may preferably be employed to inhibit glycogenolysis,thereby interrupting or modulating hepatic glucose production.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to, treating,preventing or slowing the progression of diabetes and related conditions(such as hyperglycemia, impaired glucose tolerance, insulin resistanceand hyperinsulinemia), the microvascular complications associated withdiabetes (such as retinopathy, neuropathy, nephropathy and delayed woundhealing), the macrovascular complications associated with diabetes(cardiovascular diseases such as atherosclerosis, abnormal heartfunction, myocardial ischemia and stroke), as well as Metabolic Syndromeand its component conditions including hypertension, obesity anddislipidemia (including hypertriglyceridemia, hypercholesterolemia andlow HDL), and other maladies such as non-cardiac ischemia, infection andcancer.

Metabolic Syndrome or “Syndrome X” is described in Ford, et al., J. Am.Med. Assoc. 2002, 287, 356-359 and Arbeeny, et al., Curr. Med.Chem.—Imm., Endoc. & Metab. Agents 2001, 1, 1-24.

B. Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other compounds of the invention, or in combination with one ormore other therapeutic agent(s), e.g., an antidiabetic agent or otherpharmaceutically active material.

The compounds of the present invention may employed in combination withother glycogen phosphorylase inhibitors or one or more other suitabletherapeutic agents useful in the treatment of the aforementioneddisorders including: anti-diabetic agents; anti-atherosclerotic agents;anti-ischemic agents; anti-infective agents; anti-cancer and cytotoxicagents; anti-hyperglycemic agents; lipid lowering agents;anti-hypertensive agents; anti-obesity agents and appetite suppressants.

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include insulin and insulinanalogs: LysPro insulin, inhaled formulations comprising insulin;glucagon-like peptides; sulfonylureas and analogs: chlorpropamide,glibenclamide, tolbutamide, tolazamide, acetohexamide, glypizide,glyburide, glimepiride, repaglinide, meglitinide; biguanides: metformin,phenformin, buformin; alpha2-antagonists and imidazolines: midaglizole,isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulinsecretagogues: linogliride, insulinotropin, exendin-4, BTS-67582,A-4166; thiazolidinediones: ciglitazone, pioglitazone, troglitazone,rosiglitazone; PPAR-gamma agonists; PPAR-alpha agonists; PPARalpha/gamma dual agonists; SGLT2 inhibitors; dipeptidyl peptidase-IV(DPP4) inhibitors; aldose reductase inhibitors; RXR agonists: JTT-501,MCC-555, MX-6054, DRF2593, GI-262570, KRP-297, LG100268; fatty acidoxidation inhibitors: clomoxir, etomoxir; α-glucosidase inhibitors:precose, acarbose, miglitol, emiglitate, voglibose, MDL-25,637,camiglibose, MDL-73,945; beta-agonists: BRL 35135, BRL 37344, Ro16-8714, ICI D7114, CL 316,243, TAK-667, AZ40140; phosphodiesteraseinhibitors, both cAMP and cGMP type: sildenafil, L686398: L-386,398;amylin antagonists: pramlintide, AC-137; lipoxygenase inhibitors:masoprocal; somatostatin analogs: BM-23014, seglitide, octreotide;glucagon antagonists: BAY 276-9955; insulin signaling agonists, insulinmimetics, PTP1B inhibitors: L-783281, TER17411, TER17529;gluconeogenesis inhibitors: GP3034; somatostatin analogs andantagonists; antilipolytic agents: nicotinic acid, acipimox, WAG 994;glucose transport stimulating agents: BM-130795; glucose synthase kinaseinhibitors: lithium chloride, CT98014, CT98023 and galanin receptoragonists.

Other suitable thiazolidinediones include Mitsubishi's MCC-555(disclosed in U.S. Pat. No. 5,594,016), Glaxo-Welcome's GL-262570,englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer,isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702(Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi).

Suitable PPAR alpha/gamma dual agonists include AR-HO39242(Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck) aswell as those disclosed by Murakami et al, “A Novel Insulin SensitizerActs As a Coligand for Peroxisome Proliferation—Activated Receptor Alpha(PPAR alpha) and PPAR gamma; Effect of PPAR alpha Activation on AbnormalLipid Metabolism in Liver of Zucker Fatty Rats”, Diabetes 47, 1841-1847(1998), and WO 01/21602, the disclosure of which is incorporated hereinby reference, employing dosages as set out therein, which compoundsdesignated as preferred are preferred for use herein.

Suitable alpha2 antagonists also include those disclosed in WO 00/59506,employing dosages as set out herein.

Suitable SGLT2 inhibitors include T-1095, phlorizin, WAY-123783 andthose described in WO 01/27128.

Suitable DPP4 inhibitors include those disclosed in WO99/38501,WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431(PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) as disclosed by Hughes et al, Biochemistry, 38 (36),11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540,2-cyanopyrrolidides and 4-cyanopyrrolidides, as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996) employing dosages as set out in the above references.

Suitable aldose reductase inhibitors include those disclosed in WO99/26659.

Suitable meglitinides include nateglinide (Novartis) or KAD1229(PF/Kissei).

Examples of glucagon-like peptide-1 (GLP-1) include GLP-1 -(1-36) amide,GLP-1 (7-36) amide, GLP-1 (7-37) (as disclosed in U.S. Pat. No.5,614,492 to Habener), as well as AC2993 (Amylen) and LY-315902 (Lilly).

Other anti-diabetic agents that can be used in combination withcompounds of the invention include ergoset and D-chiroinositol.

Suitable anti-ischemic agents include, but are not limited to, thosedescribed in the Physicians' Desk Reference and NHE inhibitors,including those disclosed in WO 99/43663.

Examples of suitable anti-infective agents are antibiotic agents,including, but not limited to, those described in the Physicians' DeskReference.

Examples of suitable lipid lowering agents for use in combination withthe compounds of the present invention include one or more MTPinhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, upregulators of LDL receptor activity, bileacid sequestrants, cholesterol ester transfer protein inhibitors (e.g.,CP-529414 (Pfizer)) and/or nicotinic acid and derivatives thereof.

MTP inhibitors which may be employed as described above include thosedisclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat.No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S.Pat. No. 5,885,983 and U.S. Pat. No. 5,962,440.

The HMG CoA reductase inhibitors which may be employed in combinationwith one or more compounds of formula I include mevastatin and relatedcompounds, as disclosed in U.S. Pat. No. 3,983,140, lovastatin(mevinolin) and related compounds, as disclosed in U.S. Pat. No.4,231,938, pravastatin and related compounds, such as disclosed in U.S.Pat. No. 4,346,227, simvastatin and related compounds, as disclosed inU.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductaseinhibitors which may be employed herein include, but are not limited to,fluvastatin, disclosed in U.S. Pat. No. 5,354,772, cerivastatin, asdisclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080, atorvastatin, asdisclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and5,686,104, atavastatin (Nissan/Sankyo's nisvastatin (NK-104)), asdisclosed in U.S. Pat. No. 5,011,930, visastatin (Shionogi-Astra/Zeneca(ZD-4522)), as disclosed in U.S. Pat. No. 5,260,440, and related statincompounds disclosed in U.S. Pat. No. 5,753,675, pyrazole analogs ofmevalonolactone derivatives, as disclosed in U.S. Pat. No. 4,613,610,indene analogs of mevalonolactone derivatives, as disclosed in PCTapplication WO 86/03488,6-[2-(substituted-pyrrol-1-yl)alkyl)pyran-2-ones and derivativesthereof, as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone, as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives, as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives, as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone, as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes, such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin), as disclosed inEuropean Patent Application No. 0142146 A2, and quinoline and pyridinederivatives, as disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, atavastatin and ZD-4522.

In addition, phosphinic acid compounds useful in inhibiting HMG CoAreductase, such as those disclosed in GB 2205837, are suitable for usein combination with the compounds of the present invention.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol.31, No. 10, pp 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates, as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. No.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,109, 5544 and cyclopropanes reported by Capson, T. L., Ph.D.dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table ofContents, pp. 16, 17, 40-43, 48-51, Summary.

The fibric acid derivatives which may be employed in combination withone or more compounds of formula I include fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like,probucol, and related compounds, as disclosed in U.S. Pat. No.3,674,836, probucol and gemfibrozil being preferred, bile acidsequestrants, such as cholestyramine, colestipol and DEAE-Sephadex(Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), EisaiE-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402),tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche),aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulenederivative), melinamide (Sumitomo), Sandoz 58-035, American CyanamidCL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinicacid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,poly(diallylmethylamine) derivatives, such as disclosed in U.S. Pat. No.4,759,923, quaternary amine poly(diallyldimethylammonium chloride) andionenes, such as disclosed in U.S. Pat. No. 4,027,009, and other knownserum cholesterol lowering agents.

The ACAT inhibitor which may be employed in combination with one or morecompounds of formula I include those disclosed in Drugs of the Future24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, C1-1011 is effectivein the prevention and regression of aortic fatty streak area inhamsters”, Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998),137(1), 77-85; “The pharmacological profile of FCE 27677: a novel ACATinhibitor with potent hypolipidemic activity mediated by selectivesuppression of the hepatic secretion of ApoB100-containing lipoprotein”,Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; “RP73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”,Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACATinhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem.(1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd.).

The hypolipidemic agent may be an upregulator of LD2 receptor activity,such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

Examples of suitable cholesterol absorption inhibitor for use incombination with the compounds of the invention include SCH48461(Schering-Plough), as well as those disclosed in Atherosclerosis 115,45-63 (1995) and J. Med. Chem. 41, 973 (1998).

Examples of suitable ileal Na⁺/bile acid cotransporter inhibitors foruse in combination with the compounds of the invention include compoundsas disclosed in Drugs of the Future, 24, 425-430 (1999).

The lipoxygenase inhibitors which may be employed in combination withone or more compounds of formula I include 15-lipoxygenase (15-LO)inhibitors, such as benzimidazole derivatives, as disclosed in WO97/12615, 15-LO inhibitors, as disclosed in WO 97/12613, isothiazolones,as disclosed in WO 96/38144, and 15-LO inhibitors, as disclosed bySendobry et al “Attenuation of diet-induced atherosclerosis in rabbitswith a highly selective 15-lipoxygenase inhibitor lacking significantantioxidant properties”, Brit. J. Pharmacology (1997) 120, 1199-1206,and Comicelli et al, “15-Lipoxygenase and its Inhibition: A NovelTherapeutic Target for Vascular Disease”, Current Pharmaceutical Design,1999, 5, 11-20.

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include beta adrenergicblockers, calcium channel blockers (L-type and T-type; e.g. diltiazem,verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g.,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetamide, triamtrenene, amiloride,spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril,zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists(e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g.,sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos.5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compoundsdisclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), and nitrates.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include a cannabinoid receptor 1antagonist or inverse agonist, a beta 3 adrenergic agonist, a lipaseinhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroidreceptor beta drug and/or an anorectic agent.

Cannabinoid receptor 1 antagonists and inverse agonists which may beoptionally employed in combination with compounds of the presentinvention include rimonabant, SLV 319 and those discussed in D. L.Hertzog, Expert Opin. Ther. Patents 2004, 14, 1435-1452.

The beta 3 adrenergic agonists which may be optionally employed incombination with compounds of the present invention include AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer,) or otherknown beta 3 agonists, as disclosed in U.S. Pat. Nos. 5,541,204,5,770,615, 5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 andCP331648 being preferred.

Examples of lipase inhibitors which may be optionally employed incombination with compounds of the present invention include orlistat orATL-962 (Alizyme), with orlistat being preferred.

The serotonin (and dopoamine) reuptake inhibitor which may be optionallyemployed in combination with a compound of formula I may be sibutramine,topiramate (Johnson & Johnson) or axokine (Regeneron), with sibutramineand topiramate being preferred.

Examples of thyroid receptor beta compounds which may be optionallyemployed in combination with compounds of the present invention includethyroid receptor ligands, such as those disclosed in WO97/21993 (U. CalSF) and WO99/00353 (KaroBio), with compounds of the KaroBio applicationsbeing preferred.

The anorectic agent which may be optionally employed in combination withcompounds of the present invention include dexamphetamine, phentermine,phenylpropanolamine or mazindol, with dexamphetamine being preferred.

Other compounds that can be used in combination with the compounds ofthe present invention include CCK receptor agonists (e.g., SR-27895B);galanin receptor antagonists; MCR-4 antagonists (e.g., HP-228); leptinor mimentics; 1-beta-hydroxysteroid dehydrogenase type-1 inhibitors;urocortin mimetics, CRF antagonists, and CRF binding proteins (e.g.,RU-486, urocortin).

Further, the compounds of the present invention may be used incombination with anti-cancer and cytotoxic agents, including but notlimited to alkylating agents such as nitrogen mustards, alkylsulfonates, nitrosoureas, ethylenimines, and triazenes; antimetabolitessuch as folate antagonists, purine analogues, and pyrimidine analogues;antibiotics such as anthracyclines, bleomycins, mitomycin, dactinomycin,and plicamycin; enzymes such as L-asparaginase; farnesyl-proteintransferase inhibitors; 5α reductase inhibitors; inhibitors of17β-hydroxy steroid dehydrogenase type 3; hormonal agents such asglucocorticoids, estrogens/antiestrogens, androgens/antiandrogens,progestins, and luteinizing hormone-releasing hormone antagonists,octreotide acetate; microtubule-disruptor agents, such as ecteinascidinsor their analogs and derivatives; microtubule-stabilizing agents such astaxanes, for example, paclitaxel (Taxol®), docetaxel (Taxotere®), andtheir analogs, and epothilones, such as epothilones A-F and theiranalogs; plant-derived products, such as vinca alkaloids,epipodophyllotoxins, taxanes; and topiosomerase inhibitors;prenyl-protein transferase inhibitors; and miscellaneous agents such ashydroxyurea, procarbazine, mitotane, hexamethylmelamine, platinumcoordination complexes such as cisplatin and carboplatin; and otheragents used as anti-cancer and cytotoxic agents such as biologicalresponse modifiers, growth factors; immune modulators and monoclonalantibodies. Additional anti-cancer agents are disclosed in EP 1177791.The compounds of the invention may also be used in conjunction withradiation therapy.

The aforementioned patents and patent applications are incorporatedherein by reference.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physician's Desk Reference, as in thepatents set out above or as otherwise determined by one of ordinaryskill in the art.

The compounds of the formula I can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such as inthe form of tablets, capsules, granules or powders; sublingually;bucally; parenterally, such as by subcutaneous, intravenous,intramuscular, or intrastemal injection or infusion techniques (e.g., assterile injectable aqueous or non-aqueous solutions or suspensions);nasally, including administration to the nasal membranes, such as byinhalation spray; topically, such as in the form of a cream or ointment;or rectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents.

In carrying out the method of the invention for treating diabetes andrelated diseases, a pharmaceutical composition will be employedcontaining the compounds of formula I, with or without otherantidiabetic agent(s) and/or antihyperlipidemic agent(s) and/or othertype therapeutic agents in association with a pharmaceutical vehicle ordiluent. The pharmaceutical composition can be formulated employingconventional solid or liquid vehicles or diluents and pharmaceuticaladditives of a type appropriate to the mode of desired administration,such as pharmaceutically acceptable carriers, excipients, binders andthe like. The compounds can be administered to a mammalian patient,including humans, monkeys, dogs, etc. by an oral route, for example, inthe form of tablets, capsules, beads, granules or powders. Typical solidformulations will contain from about 1 to about 1000 mg of a compound offormula I. The dose for adults is preferably between 1 and 2,000 mg perday, which can be administered in a single dose or in the form ofindividual doses from 1-4 times per day.

It will be understood that the specific dose level and frequency ofdosage for any particular subject can be varied and will depend upon avariety of factors including the potency of the specific compoundemployed, the metabolic stability and length of action of that compound,the species, age, body weight, general health, sex and diet of thesubject, the mode and time of administration, rate of excretion, drugcombination, and severity of the particular condition.

Glycogen phosphorylase inhibitor activity of the compounds of theinvention may be determined by use of an assay system as set out below.

Assay for Glycogen Phosphorylase Activity

The utility of the compounds of the invention for use in the treatmentof diabetes and the other conditions that may be treated with a glycogenphosphorylase inhibitor may be demonstrated in assays for glycogenphosphorylase inhibition in vitro (U.S. Pat. No. 6,107,329), effects onblood sugar and insulin in vivo (U.S. Pat. No. 6,107,329), effects onischemic tissue damage in vitro (U.S. Pat. No. 6,107,329), and effectson weight and food intake in vivo (WO 00/47206). Compounds deemed hereinto possess activity as inhibitors of the enzyme glycogen phosphorylasedemonstrate an IC₅₀ of 10 μM or lower when measured in theaforementioned glycogen phosphorylase inhibition in vitro assay.

EXAMPLES

The following working Examples serve to better illustrate, but notlimit, some of the preferred embodiments of the present invention.

General

Reverse phase preparative HPLC separation employed an octadecyl sulfate(C-18) column eluting with a solvent gradient of solvents A and B,starting with 20% or more of solvent B and finishing with 100% ofsolvent B. Solvent A was 10% methanol in water, and solvent B was 90%methanol in water. In many cases both solvents A and B contained 0.1% oftrifluoroacetic acid, as noted. Reverse phase analyrical HPLC employedthe same type of column and solvents, except that the solvents contained0.2% phosphoric acid.

For Examples 1 to 4 see Table 1: TABLE 1

Example R¹ 1 OH 2 CO₂H 3 CONMe₂ 4 NHCOCO₂H

Example 1 5-Chloro-1H-indole-2-carboxylic acid(3-hydroxynaphthalen-2-yl)amide

To a stirred solution of 5-chloroindole-2-carboxylic acid (86 mg, 0.44mmol) in tetrahydrofuran (2 mL) at room temperature under nitrogen wasadded oxalyl chloride (2.0 M in dichloromethane solution, 0.45 mL, 0.90mmol) and N,N-dimethylformamide (0.010 mL). After 1 h, the reactionmixture was concentrated under vacuum to provide the acid chloride,which was taken up in tetrahydrofuran (3 mL). To the resulting solutionstirring under nitrogen at room temperature was added 3-amino-2-naphthol(70 mg, 0.44 mmol) followed by triethylamine (0.3 mL, 2.2 mmol). After 1h, the reaction mixture was quenched by addition of 1.0 M aqueoushydrochloric acid solution and diluted with ethyl acetate. The reactionmixture was filtered to remove insoluble materials. The filtrate waswashed sequentially with 1.0 M aqueous hydrochloric acid solution andbrine, dried over anhydrous magnesium sulfate, and concentration undervacuum to yield a residue. The residue was suspended in methanol and themethanol solution phase was purified by reverse phase preparative HPLC(trifluoroacetic acid containing solvents were used) to obtain Example 1(16 mg, 11%) as a light yellow solid. ¹H NMR (400 MHz,d₈-tetrahydrofuran) δ 9.61 (s, 1H), 9.13 (s, 1H), 8.79 (s, 1H), 7.74 (d,J=7.0 Hz, 1H), 7.66 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.45 (d, J=7.2 Hz,1H), 7.19 (m, 4H), 7.17 (s, 1H), 7.13 (s, 1H). MS [M+H]⁺, 337; [M−H]⁻,335.

Example 23-[(5-Chloro-1H-indole-2-carbonyl)amino]naphthalene-2-carboxylic acid

To a stirred solution of 5-chloroindole-2-carboxylic acid (300 mg, 1.53mmol) in tetrahydrofuran (10 mL) at room temperature under nitrogen wasadded oxalyl chloride (2.0 M in dichloromethane solution, 1.53 mL, 3.06mmol) and N,N-dimethylformamide (0.010 mL). After 1.5 h, the reactionmixture was concentrated under vacuum to yield the acid chloride. Theacid chloride was dissolved in tetrahydrofuran (10 mL) stirring undernitrogen at room temperature, and 3-amino-2-naphthoic acid (287 mg, 1.53mmol) was added followed by triethylamine (1.1 mL, 7.7 mmol). After 2 h,the reaction mixture was quenched by addition of 1.0 M aqueoushydrochloric acid solution and diluted with ethyl acetate. The organiclayer was washed sequentially with 1.0 M aqueous hydrochloric acidsolution, saturated aqueous sodium bicarbonate solution, saturatedaqueous ammonium chloride solution and brine, dried over anhydrousmagnesium sulfate, and concentrated under vacuum to yield a residue. Theresidue was suspended in methanol and filtered to collect Example 2 (300mg, 54%) as a light yellow solid. ¹H NMR (500 MHz, d₈-tetrahydrofuran) δ12.42 (s, 1H), 11.38 (s, 1H), 9.33 (s, 1H), 8.79 (s, 1H), 7.91 (d, J=7.5Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.68 (s, 1H), 7.57 (t, J=6.6 Hz, 1H),7.45 (m, 2H), 7.21 (d, J=6.5 Hz, 1H), 7.13 (s, 1H). HPLC/MS [M+H]⁺, 365;[M−H]⁻, 363.

Example 3 5-Chloro-1H-indole-2-carboxylic acid(3-dimethylcarbamoylnaphthalen-2-yl)amide

To a stirred solution of Example 2 (45 mg, 0.12 mmol) in tetrahydrofuran(3 mL) at room temperature under nitrogen was added oxalyl chloride (2.0M in dichloromethane solution, 0.12 mL, 0.24 mmol) andN,N-dimethylformamide (0.010 mL). After 1 h, the reaction mixture wasconcentrated under vacuum to yield the acid chloride. The acid chloridewas dissolved in tetrahydrofuran (3 mL) stirring under nitrogen at roomtemperature, and N,N-dimethylformamide (1.5 mL) and dimethylaminehydrochloride (20 mg, 0.24 mmol),1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (47 mg,0.24 mmol), 1-hydroxy-7-azabenzotriazole (33 mg, 0.24 mmol) anddiisopropylethylamine (0.2 mL, 1.2 mmol) were added. The reactionmixture was stirred for 16 h before dilution with ethyl acetate. Theorganic layer was washed sequentially with 1.0 M aqueous hydrochloricacid solution, 1.0 M aqueous sodium hydroxide solution and brine, driedover anhydrous magnesium sulfate, and concentrated under vacuum to yielda residue. The residue was suspended in methanol and filtered to collectExample 3 (39 mg, 81%) as a light yellow solid. ¹H NMR (400 MHz,d₈-tetrahydrofuran) δ 12.02 (s, 1H), 10.50 (s, 1H), 8.22 (s, 1H), 8.00(s, 1H), 7.97 (t, J=7.5 Hz, 1H), 7.79 (s, 1H), 7.55 (m, 2H), 7.47 (d,J=7.8 Hz, 1H), 7.24 (m, 3H), 3.03 (s, 3H), 3.00 (s, 3H). MS [M+H]⁺, 392;[M−H]⁻, 390.

Example 4N-{3-[(5-Chloro-1H-indole-2-carbonyl)amino]naphthalen-2-yl}oxalamic acidPart I: 2-Amino-3-(5-chloroindole-2-carbonylamino)naphthalene

A solution of 5-chloroindole-2-carboxylic acid (247 mg),2,3-diaminonaphthalene (200 mg), 1-hydroxybenzotriazole hydrate (221mg), 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (315mg) and triethylamine (447 mg) in N,N-dimethylformamide was stirredunder nitrogen at room temperature for 3 h. The reaction mixture wasdiluted with water before extraction with ethyl acetate (three times).The combined organic extracts were washed sequentially with saturatedaqueous ammonium chloride solution, water and saturated aqueous sodiumbicarbonate solution (three times each), dried over anhydrous magnesiumsulfate and evaporated under vacuum to yield a solid. The solid wastriturated with chloroform and then dried under vacuum to obtain thetitle compound as a tan solid (102 mg).

Part II:N-{3-[(5-Chloro-1H-indole-2-carbonyl)amino]naphthalen-2-yl}oxalamic acidethyl ester

To a solution of 2-amino-3-(5-chloroindole-2-carbonylamino)naphthalene(50 mg) in tetrahydrofuran (<1 mL) stirring at room temperature underargon, was added ethyl oxalyl chloride (40 mg) followed by triethylamine(34 mg). After 2 h, the reaction mixture was diluted with water and thenextracted with ethyl acetate (three times). The combined organicextracts were dried over anhydrous magnesium sulfate and evaporatedunder vacuum to yield a residue. The residue was subjected to silica gelchromatography eluted with 30% ethyl acetate in hexane to obtain thetitle compound.

Part III: Example 4

To a solution ofN-{3-[(5-chloro-1H-indole-2-carbonyl)amino]naphthalen-2-yl}oxalamic acidethyl ester (15 mg) in methanol and tetrahydrofuran (1:1, 0.4 mL),stirring at room temperature, was added 1.0 M aqueous sodium hydroxidesolution (0.04 mL). After 2 h, 1.0 M aqueous hydrochloric acid solutionwas added to acidify to pH 2-3, and the mixture was purified directly byreverse phase preparative HPLC (trifluoroacetic acid containing solventswere used) to obtain Example 4 as a yellow solid. HPLC/MS [M+H]⁺, 408.

Example 53-[(5-Chloro-1H-indole-2-carbonyl)amino]naphthalene-1-carboxylic acid

To a stirring solution of 5-chloroindole-2-carboxylic acid (0.20 g) intetrahydrofuran (1.5 mL) at room temperature under argon was addedoxalyl chloride (2.0 M in dichloromethane, 0.5 mL), followed byN,N-dimethylformamide (1 drop). The solution bubbled for 10 min. After 2h, a small sample of the solution was quenched with methanol and thenanalyzed by HPLC/MS, which indicated that at least 75% of the acid hadbeen converted to acid chloride (based on observation of both the acidchloride itself and its methyl ester). In a separate reaction vessel,3-amino-1-carboxynaphthalene hydrochloride (prepared in the mannerdescribed in P. Parik, Collect. Czech. Chem. Commun. 2000, 65, 385-394,0.24 g) was slurried in tetrahydrofuran (5 mL) at room temperature underargon. The resulting mixture was stirred as diisopropylethylamine (0.74g) was added. A poorly soluble gum formed. To this gum was added thesolution of acid chloride prepared above. The gum was dissolved and asolid precipitate slowly formed. The resulting mixture was analyzed byHPLC/MS, which indicated the formation of both desired product andbisacylation product in a 1:1 ratio. Tetrahydrofuran (10 mL) was added,and the resulting mixture (pH 11) was refluxed for 1 h. After this time,the mixture was again analyzed by HPLC/MS, which indicated the ratio ofdesired product to bisacylation product was 7:1. The mixture was cooledroom temperature. Once at room temperature, 1.0 M aqueous hydrochloricacid solution (6 μL) and water (35 mL) were added to achieve a pH of 1,and stirring was discontinued. Some solid and oil formed and settled.The supernatant was removed and discarded. The solid and oil werestirred with water, which caused the oil to solidify. Again, thesupernatant was removed and discarded. The solid was briefly boiled inmethanol, and after cooling to room temperature, the supernatant extractwas collected. This methanol extraction procedure was repeated (3times), and the combined extracts were purified by reverse phasepreparative HPLC (trifluoroacetic acid containing solvents were used) toobtain Example 5 (109 mg) as a solid. HPLC/MS [M+H]⁺, 365; [M−H]⁻, 363.

1. A compound of the formula I

or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein: W is a bicyclic heteroaryl of the structure

A is —CH— or —N—; B is —O— or —S—; R¹, which may attach at any of the three positions of the WCONH-bearing ring of the naphthalene ring system, is independently hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, alkenyl, OR^(5A), OCO₂R⁶, OCONR^(5A)R^(5B), CN, CN₄R^(5A) (tetrazole), CO₂R^(5A), CONR^(5A)R^(5B), CONR^(5A)OR^(5B), NR^(5A)COCO₂R^(5B) or another hydrogen bonding group; R², which may attach at any of the four positions on the non-WCONH-bearing ring of the naphthalene ring system, is independently hydrogen, halo, trifluoromethyl, cyano, hydroxy, another hydrogen bonding group, alkyl, aryl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy or alkenyl; R³ and R⁴ are each independently hydrogen, halo, trifluoromethyl, cyano, alkyl or alkoxy; and R^(5A) and R^(5B) are independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R^(5A) and R^(5B) may optionally be cyclized together to form a ring, wherein said ring may further be substituted with one to three additional hydrogen bonding groups; and R⁶ is alkyl, aryl, arylalkyl or heteroarylalkyl; wherein when R¹ and R² are alkyl, aryl, arylalkyl, heteroarylalkyl, alkenyl, alkoxy or aryloxy, R¹ and R² may each independently be substituted with one to three hydrogen bonding groups; with the following provisos (a) excluding compounds wherein: W is a bicyclic heteroaryl of the structure

B is —O— or —S—; R¹ is selected from hydrogen, alkyl, aryl, alkenyl, OR^(5A), CN, CN₄R^(5A) (tetrazole), CO₂R^(5A), CONR^(5A)R^(5B), or another hydrogen bonding group, wherein the hydrogen bonding group is selected from the group consisting of NO₂, COR^(5A), CO₂R^(5A), CONR^(5A)R^(5B), CONR^(5A)OR^(5B), SOR⁶, SO₂R⁶, SO₂NR^(5A)R^(5B), NR^(5A)R^(5B), NR^(5A)COR^(5B), NR^(5A)CO₂R⁶, NR^(5A)CONR^(5B)R^(5C)NR^(5A)SO₂R^(5B), and a divalent hydrogen bonding group; R² is selected from hydrogen, halo, trifluoromethyl, cyano, hydroxy, another hydrogen bonding group, alkyl, aryl, alkoxy, aryloxy or alkenyl, wherein the hydrogen bonding group is selected from the group consisting of NO₂, COR^(5A), CO₂R^(5A), CONR^(5A)R^(5B), CONR^(5A)ORB SOR⁶, SO₂R⁶, SO₂NR^(5A)R^(5B), NR^(5A)R^(5B), NR^(5A)COR^(5B), NR^(5A)CO₂R⁶, NR^(5A)CONR^(5B)R^(5C)NR^(5A)SO₂R^(5B), and a divalent hydrogen bonding group; R^(5A), R^(5B), and R^(5C) are each independently hydrogen or alkyl; R⁶ is alkyl; and R³ and R⁴ are each independently hydrogen, halo, trifluoromethyl, cyano, alkyl or alkoxy; (b) excluding compounds wherein: W is a bicyclic heteroaryl of the structure

A is —CH—; B is —S—; and One of R¹ or R² is an optionally substituted 1-hydroxyethyl moiety, an optionally substituted ethenyl group, optionally substituted COR⁵ or bromo when the other of R¹ or R² is hydrogen, alkyl, aryl, arylalkyl, OR^(5A), CN, CO₂R^(5A), halo, trifluoromethyl, hydroxyl, alkoxy, aryloxy, COF₃, COR^(5A), NH₂, NO₂ or NHCOR^(5B); (c) excluding compounds wherein: W is a bicyclic heteroaryl of the structure

A is —CH—; R¹ is independently hydrogen, C₁₋₄ alkyl, aryl, arylalkyl, heteroarylalkyl, C₂₋₄ alkenyl, OR^(5A), CN, NO₂, NR^(5A)R^(5B), or CO₂R^(5A); R² is independently hydrogen, halo, trifluoromethyl, cyano, hydroxy, NO₂, C₁₋₄alkyl, aryl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, NR^(5A)R^(5B), CO₂R^(5A) or C₂₋₄ alkenyl; R³ is independently hydrogen, halo or C₁₋₄ alkyl; R⁴ is C₁₋₄ alkoxy; and R^(5A) and R^(5B) are independently hydrogen, C₁₋₄ alkyl, or aryl; (d) excluding compounds wherein: W is a bicyclic heteroaryl of the structure

A is —CH—; R¹ is independently hydrogen, C₁₋₅ alkyl, OR^(5A), CN, NO₂, NR^(5A)R^(5B), COR^(5A), CO₂R^(5A) or CONR^(5A)R^(5B); R² is independently hydrogen, halo, trifluoromethyl, cyano, hydroxy, C₁₋₅ alkyl, C₁₋₅alkoxy, OR^(5A), NO₂, NR^(5A)R^(5B), COR^(5A), CO₂R^(5A) or CONR^(5A)R^(5B); R⁴ is C₁₋₅ alkoxy; and R^(5A) and R^(5B) are independently hydrogen or C₁₋₅ alkyl; (e) excluding compounds wherein: W is a bicyclic heteroaryl of the structure

A is —CH—; R¹ is independently hydrogen, C₁₋₆ alkyl, aryl or arylalkyl; R², which is attached at the 6^(th) position of the naphthalene ring system, is methoxy substituted with CO₂H, CN₄H (tetrazole), SO₃H or PO₃H₂ or some other acidic monovalent hydrogen bonding group; R³ and R⁴ are each independently hydrogen, halo, trifluoromethyl, C₁₋₆ alkyl or C₁₋₆ alkoxy; (f) excluding compounds wherein: W is a bicyclic heteroaryl of the structure

A is —CH—; R¹ and R² are hydrogen; R³ is halo; and R⁴ is independently hydrogen, halo, alkyl or alkoxy; and (g) excluding the compound 2-[(1H-indole-2-carbonyl)amino]naphthalene. (h) excluding compounds wherein: W is a bicyclic heteroaryl of the structure

A is —CH— or —N—; One of R¹ and R² is alkyl, alkenyl, OR^(5A) or NR^(5A)COR^(5B) substituted by CONR^(5A)R^(5B), which is itself substituted by PO₃R^(5A)R^(5B); R³ and R⁴ are each independently hydrogen, halo, trifluoromethyl, cyano, alkyl or alkoxy; and R^(5A) and R^(5B) are each C₁₋₄ alkyl.
 2. The compound of claim 1 wherein W is a bicyclic heteroaryl of the structure


3. The compound of claim 2 wherein A is —CH—; R¹ is independently substituted alkyl, OR^(5A), OCONR^(5A)R^(5B), CN, CN₄R^(5A) (tetrazole), CO₂R^(5A), CONR^(5A)R^(5B) or NR^(5A)COCO₂R^(5B); R² and R³ are hydrogen; R⁴ is halo, trifluoromethyl or cyano; and R^(5A) and R^(5B) are hydrogen or alkyl.
 4. The compound of claim 1 wherein said hydrogen bonding group is selected from the set of monovalent hydrogen bonding groups consisting of OR^(5A), OCO₂R⁶, OCONR^(5A)R^(5B), CN, NO₂, CN₄R^(5A) (tetrazole), COCF₃, COR^(5A), CO₂R^(5A), CONR^(5A)R^(5B), CONR^(5A)OR^(5B), C(NR^(5A))NR^(5B)R^(5C), CONR^(5A)SO₂R^(5B), SOR⁶, SO₂R⁶, SO₃H, SO₂NR^(5A)R^(5B), SO₂NR^(5A)COR^(5B), SO₂NR^(5A)CONR^(5B)R^(5C), POR^(5A)R^(5B), PO₂R^(5A)R^(5B), PO₃R^(5A)R, PO₂R^(5A)NR^(5B)R^(5C), NR^(5A)R^(5B), NR^(5A)COR^(5B), NR^(5A)C(NR^(5B))R^(5C), NR^(5A)CO₂R⁶, NR^(5A)COCO₂R^(5B), NR^(5A)CONR^(5B)R^(5C), NR^(5A)C(NR^(5B))NR^(5C)R^(5D) NR^(5A)SO₂R^(5B), NR^(5A)CONR^(5B)SO₂R^(5C), NR^(5A)SO₂NR^(5B)R^(5C), NR^(5A)POR^(5B)R^(5C), NR^(5A)PO₂R^(5B)R^(5C), NR^(5A)PO₃R^(5B)R^(5C) and NR^(5A)PO₂R^(5B)NR^(5C)R^(5D), or the set of divalent hydrogen bonding groups consisting of —O—, —CO—, —SO₂—, —NR^(5A)—, —CO₂—, —CONR^(5A)—, —SO₂NR^(5A)—, —OCONR^(5A), NR^(5A)CONR^(5B), —N(COR^(5A))—, —N(CO₂R^(5A))—, —N(CONR^(5A)R^(5B))— and —N(SO₂NR^(5A)R^(5B))—; wherein R^(5C) and R^(5D) are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl; and wherein R^(5A), R^(5B), R^(5C), R^(5D) or R⁶ may further be substituted with one to three additional hydrogen bonding groups; and wherein two of R^(5A), R^(5B), R^(5C) or R^(5D) within the same hydrogen bonding group may optionally be cyclized together to form a ring, wherein said ring may further be substituted with one to three additional hydrogen bonding groups.
 5. The compound of claim 1 wherein W is

A is —CH—; and R⁴ is halo, trifluoromethyl or cyano.
 6. The compound of claim 1 wherein W is 5-chloroindol-2-yl.
 7. A compound selected from the group consisting of:


8. A pharmaceutical composition comprising a compound of claim
 1. 9. A pharmaceutical composition comprised of a compound of claim
 7. 10. The pharmaceutical composition of claim 8 further comprising a pharmaceutically acceptable carrier.
 11. The pharmaceutical composition of claim 8 further comprising at least one additional therapeutic agent.
 12. A method for treating, preventing or slowing the progression of a disease requiring glycogen phosphorylase inhibitor therapy which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of the pharmaceutical composition of claim
 8. 13. The method according to claim 12 further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of other compounds of formula I, anti-diabetic agents, anti-obesity agents, anti-hypertensive agents, anti-atherosclerotic agents, anti-ischemic agents, anti-infective agents, anti-cancer agents and lipid-lowering agents.
 14. A method of inhibiting the enzyme glycogen phosphorylase which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of a compound of the formula I

or stercoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein: W is a bicyclic heteroaryl of the structure

A is —CH— or —N—; B is —O— or —S—; R¹, which may attach at any of the three positions of the WCONH-bearing ring of the naphthalene ring system, is independently hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, alkenyl, OR^(5A), OCO₂R⁶, OCONR^(5A)R^(5B), CN, CN₄R^(5A) (tetrazole), CO₂R^(5A), CONR^(5A)R^(5B), CONR^(5A)OR^(5B), NR^(5A)COCO₂R^(5B) or another hydrogen bonding group; R², which may attach at any of the four positions on the non-WCONH-bearing ring of the naphthalene ring system, is independently hydrogen, halo, trifluoromethyl, cyano, hydroxy, another hydrogen bonding group, alkyl, aryl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy or alkenyl; R³ and R⁴ are each independently hydrogen, halo, trifluoromethyl, cyano, alkyl or alkoxy; and R^(5A) and R^(5B) are independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R^(5A) and R^(5B) may optionally be cyclized together to form a ring, wherein said ring may further be substituted with one to three additional hydrogen bonding groups; and R⁶ is alkyl, aryl, arylalkyl or heteroarylalkyl; wherein when R¹ and R² are alkyl, aryl, arylalkyl, heteroarylalkyl, alkenyl, alkoxy or aryloxy, R¹ and R² may each independently be substituted with one to three hydrogen bonding groups; with the following provisos (a) excluding compounds wherein: W is a bicyclic heteroaryl of the structure

B is —O— or —S—; R¹ is selected from hydrogen, alkyl, aryl, alkenyl, OR^(5A), CN, CN₄R^(5A) (tetrazole), CO₂R^(5A), CONR^(5A)R^(5B), or another hydrogen bonding group, wherein the hydrogen bonding group is selected from the group consisting of NO₂, COR^(5A), CO₂R^(5A), CONR^(5A)R^(5B), CONR^(5A)OR^(5B), SOR⁶, SO₂R⁶, SO₂NR^(5A)R^(5B), NR^(5A)R^(5B), NR^(5A)COR^(5B), NR^(5A)CO₂R⁶, NR^(5A)CONR^(5B)R^(5C) NR^(5A)SO₂R^(5B), and a divalent hydrogen bonding group; R² is selected from hydrogen, halo, trifluoromethyl, cyano, hydroxy, another hydrogen bonding group, alkyl, aryl, alkoxy, aryloxy or alkenyl, wherein the hydrogen bonding group is selected from the group consisting of NO₂, COR^(5A), CO₂R^(5A), CONR^(5A)R^(5B), CONR^(5A)OR^(5B), SOR⁶, SO₂R⁶, SO₂NR^(5A)R^(5B), NR^(5A)R^(5B), NR^(5A)COR^(5B), NR^(5A)CO₂R⁶, NR^(5A)CONR^(5B)R^(5C)NR^(5A)SO₂R^(5B), and a divalent hydrogen bonding group; R^(5A), R^(5B), and R^(5C) are each independently hydrogen or alkyl; R⁶ is alkyl; and R³ and R⁴ are each independently hydrogen, halo, trifluoromethyl, cyano, alkyl or alkoxy; and (b) excluding compounds wherein: W is a bicyclic heteroaryl of the structure

A is —CH—; B is —S—; and One of R¹ or R² is an optionally substituted 1-hydroxyethyl moiety when the other of R¹ or R² is hydrogen, alkyl, aryl, arylalkyl, OR^(5A), CN, CO₂R^(5A), halo, trifluoromethyl, hydroxyl, alkoxy, aryloxy, COF₃, COR^(5A), NH₂, NO₂ or NHCOR^(5B).
 15. The method of claim 14 wherein W is a bicyclic heteroaryl of the structure


16. The method of claim 14 wherein A is —H—; R¹ is independently substituted alkyl, OR^(5A), OCONR^(5A)R^(5B), CN, CN₄R^(5A) (tetrazole), CO₂R^(5A), CONR^(5A)R^(5B) or NR^(5A)COCO₂R^(5B); R² and R³ are hydrogen; R⁴ is halo, trifluoromethyl or cyano; and R^(5A) and R^(5B) are hydrogen or alkyl.
 17. The method of claim 14 wherein said hydrogen bonding group is selected from the set consisting of monovalent hydrogen bonding groups consisting of OR^(5A), OCO₂R⁶, OCONR^(5A)R^(5B), CN, NO₂, CN₄R^(5A) (tetrazole), COCF₃, COR^(5A), CO₂R^(5A), CONR^(5A)R^(5B), CONR^(5A)OR^(5B), C(NR^(5A))NR^(5B)R^(5C), CONR^(5A)SO₂R^(5B), SOR⁶, SO₂R⁶, SO₃H, SO₂NR^(5A)R^(5B), SO₂NR^(5A)COR^(5B), SO₂NR^(5A)CONR^(5B)R^(5C), POR^(5A)R^(5B), PO₂R^(5A)R^(5B), PO₃R^(5A)R^(5B), PO₂R^(5A)NR^(5B)R^(5C), NR^(5A)R^(5B), NR^(5A)COR^(5B), NR^(5A)C(NR^(5B))R^(5C), NR^(5A)CO₂R⁶, NR^(5A)COCO₂R^(5B), NR^(5A)CONR^(5B)R^(5C), NR^(5A)C(NR^(5B))NR^(5C)R^(5D), NR^(5A)SO₂R^(5B), NR^(5A)CONR^(5B)SO₂R^(5C), NR^(5A)SO₂NR^(5B)R^(5C), NR^(5A)POR^(5B)R^(5C), NR^(5A)PO₂R^(5B)R^(5C), NR^(5A)POR^(5A)R^(5B)R^(5C) and NR^(5A)PO₂R^(5B)NR^(5C)R^(5D), or the set of divalent hydrogen bonding groups consisting of —O—, —CO—, —SO₂—, —NR^(5A)—, —CO₂—, —CONR^(5A)—, —SO₂NR^(5A), —OCONR^(5A)—, —NR^(5A)CONR^(5B)—, —N(COR^(5A))—, —N(CO₂R^(5A))—, —N(CONR^(5A)R^(5B))— and —N(SO₂NR^(5A)R^(5B))—; wherein R^(5C) and R^(5D) are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl; and wherein R^(5A), R^(5B), R^(5C), R^(5D) or R⁶ may further be substituted with one to three additional hydrogen bonding groups; and wherein two of R^(5A), R^(5B), R^(5C) or R^(5D) within the same hydrogen bonding group may optionally be cyclized together to form a ring, wherein said ring may further be substituted with one to three additional hydrogen bonding groups.
 18. The method of claim 14 wherein W is

A is —H—; and R⁴ is halo, trifluoromethyl or cyano.
 19. The method of claim 14 wherein W is 5-chloroindol-2-yl.
 20. A method of inhibiting the enzyme glycogen phosphorylase which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of a compound of claim
 7. 